PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “Melphalan”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources
PubMed1990

Alkylation of DNA by melphalan in relation to immunoassay of melphalan-DNA adducts: characterization of mono-alkylated and cross-linked products from reaction of melphalan with dGMP and GMP.

A product expected to result from cross-linking of guanine bases in DNA by melphalan (4-(2-(di-guanin-7-yl))ethylamino-L-phenylalanine) was obtained from hydrolysis of melphalan-treated sodium deoxyguanylate at pH7 and characterized by U.V. and mass spectra. When tested in a competitive immunoassay using an antibody specific for melphalan-alkylated DNA it showed an affinity intermediate between that of melphalan-alkylated DNA and melphalan. From this and other assays it seemed possible that the cross-linked moiety in DNA was recognised by the antibody, but that its conformation differed from that of the free base tested, sufficiently to account for the discrepancy. It seemed possible that cross-linked guanine nucleotides would provide a better model, and these were therefore isolated, characterised and tested. Products derived from cross-linking of guanylic acid moieties through N-7 and N-7, and through N-7 and phosphate, had higher affinity than the cross-linked base, approximately the same as for alkylated native DNA, but less than for alkylated denatured DNA or RNA.

Alkylation↗
PubMed1992

Hyperthermia-induced enhancement of melphalan activity against a melphalan-resistant human rhabdomyosarcoma xenograft.

The effects of regional hyperthermia (42 degrees C for 70 min) on the antitumor activity of melphalan were examined in athymic mice bearing melphalan-resistant human rhabdomyosarcoma (TE-671 MR) xenografts growing in the right hind limb, and results were compared with similar studies of melphalan-sensitive (TE-671) parent xenografts. Melphalan alone at a dose of 36 mg/m2 (0.5 of the 10% lethal dose) produced growth delays of 4.1 to 10.2 days in TE-671 MR xenografts and 21.8 to 28.7 days in TE-671, respectively. Hyperthermia alone produced growth delays of 0.9 days in TE-671 MR xenografts and 0.8 days in TE-671. Combination therapy with melphalan and hyperthermia produced growth delays of 7.2 to 13.3 days in TE-671 MR xenografts and 34.3 to 42.8 days in TE-671, respectively, representing a mean thermal enhancement ratio of 1.7 in TE-671 MR and 1.5 in TE-671. Measurement of glutathione levels in TE-671 MR xenografts following treatment with melphalan, hyperthermia, or melphalan plus hyperthermia revealed significant reductions in glutathione content with the nadir (60% of control values) seen 6 h following treatment. Glutathione levels in TE-671 xenografts following identical therapy revealed no differences from control values. Hyperthermia plus melphalan did not result in a higher tumor-to-plasma melphalan ratio compared with treatment with melphalan alone in either TE-671 MR or TE-671 xenografts. These studies suggest that heat-induced alterations in tumor glutathione or melphalan levels are not responsible for the increase in melphalan activity produced by hyperthermia. Combination therapy with melphalan plus regional hyperthermia offers promise for treatment of melphalan-resistant neoplasms.

Animals↗
PubMedDate not supplied

Phase I study of melphalan alone and melphalan plus whole body hyperthermia in dogs with malignant melanoma.

The maximum tolerated dose of melphalan combined with whole body hyperthermia (WBH) in dogs with spontaneous malignant melanoma was lower than in dogs not receiving WBH by a factor of 1.9 +/- 0.71. Thirty-three dogs were treated monthly with escalating doses of melphalan and followed weekly for toxicity and, when possible, tumour response. Toxicity was manifested as myelosuppression with nadir neutrophil and platelet counts occurring at 7-10 days post-treatment. The TD50 (+/- S.E.), defined by logistic regression analysis, was 0.63 (+/- 0.07) mg/kg and 0.33 (+/- 0.10) mg/kg for melphalan alone and combined with WBH, respectively. Objective tumour response in this limited series occurred in three of fourteen evaluable dogs (three of eleven treated with melphalan alone and none of three treated with WBH plus melphalan). It is concluded that melphalan combined with WBH can be safely administered, although a reduction in dose is necessary. A randomized clinical trial is required to investigate the possibility of achieving therapeutic benefit from combined melphalan and WBH.

Animals↗
PubMed1986

Therapy of stage III (optimal) epithelial carcinoma of the ovary with melphalan or melphalan plus Corynebacterium parvum (a Gynecologic Oncology Group Study).

A randomized prospective therapy trial in patients with stage III optimal epithelial carcinoma of the ovary was accomplished by the Gynecologic Oncology Group. Therapy with melphalan or melphalan plus immuno-adjuvant, Corynebacterium parvum (C. parvum), was utilized as adjuvant treatment following surgical therapy. One hundred eight-five patients were eligible for evaluation with 87 patients in the melphalan group and 98 patients in the melphalan plus C. parvum group. The comparison of the treatment regimens showed no differences with respect to either progression-free interval or survival. However, it should be noted that a 50% 3-year survival was obtained. A group was identified, using four prognostic factors that had 80% survival at 3 years. Maximum size of the residual tumor, as well as performance status, was not prognostically significant. This study demonstrates a lack of efficacy of the addition of C. parvum to melphalan for this patient population.

Adult↗
PubMed1979

Amino acid conferred protection against melphalan interference with melphalan therapy by L-leucine, a competitive substrate for transport.

Melphalan uptake by L1210 leukemia cells obtained from tumor bearing mice is reduced to one-third of control by physiological concentrations of L-leucine. Kinetic analysis revealed that melphalan and leucine compete for transport carrier sites. Administration of leucine with optimal therapeutic doses of melphalan to tumor bearing mice negated the efficacy of the drug.

Animals↗
PubMed1979

Amino acid conferred protection against melphalan: comparison of amino acids which reduce melphalan toxicity to murine bone marrow precursor cells (CFU-C) and murine L1210 leukemia cells.

The effect of the naturally occuring amino acids upon melphalan (L-phenylalanine mustard, L-PAM) toxicity to a host sensitive tissue, the granulocyte and macrophage precursor cells of murine bone marrow (CFU-C), was investigated. At physiological concentrations the L isomers of leucine and glutamine were found to be the most effective of the naturally occurring amino acids in reducing drug toxicity. Tyrosine, phenylalanine and methionine also protected murine CFU-C from melphalan toxicity although the amount of protection provided by these amino acids at physiological concentrations was less than that provided by leucine and glutamine. Little difference was observed in the pattern of amino acid protection of murine CFU-C and murine L1210 leukemia cells. Murine CFU-C however were more sensitive to melphalan both in the absence and presence of amino acids.

Amino Acids↗
PubMed1990

Melphalan and prednisone (MP) versus vincristine, BCNU, adriamycin, melphalan and dexamethasone (VBAMDex) therapy for multiple myeloma. Early results of a multicenter trial. The German Myeloma Treatment Group.

136 untreated multiple myeloma patients of stage II and III were collected in the study. 37/51 stage II patients had progressive disease and were treated with melphalan and prednisone (MP). 85 patients were of stage III and randomized into MP and vincristine, BCNU, adriamycin, melphalan and dexamethasone (VBAMDex) treatment groups. 55% of MP treated patients responded versus 75% of the VBAMDex group. Since the study has been activated only 16 months ago, no difference in survival could be observed.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1987

Second-line chemotherapy of stage III-IV ovarian carcinoma: a randomized comparison of melphalan to melphalan and hexamethylmelamine in patients with persistent disease after doxorubicin and cisplatin.

A total of 205 women with stage III or IV ovarian cancer who had persistent disease after initial treatment with doxorubicin and cisplatin were randomized to receive melphalan (8 mg/m2 orally for 4 days) or the combination of melphalan (6 mg/m2 for 4 days) and hexamethylmelamine (120 mg/m2 for 14 days) every 4 weeks. Only one of 64 patients with measurable disease had an objective response. The major determinants of survival after randomization were the amount of residual disease after initial chemotherapy and the type of response to initial chemotherapy. There was no overall difference in survival between the two chemotherapy regimens, but the small group of patients whose disease progressed on initial chemotherapy survived significantly longer when treated with the two-drug combination. Neither of these regimens provided effective therapy for women whose disease was not eliminated by first-line treatment. However, the superior results obtained in one subgroup with the addition of hexamethylmelamine suggest that the place of this agent in treating ovarian cancer should be carefully evaluated.

Adult↗
PubMed1985

Thermochemotherapy with cis-platinum, CCNU, BCNU, chlorambucil and melphalan on murine marrow and two tumours: therapeutic gain for melphalan only.

The magnitude of potentiation by whole body hyperthermia (45 min at 41 degrees C) of cis-platinum (DDP), CCNU, BCNU, chlorambucil and melphalan (Mel) on two tumours was compared with that on marrow in C3H mice. Drug damage was assayed in the KHT tumour by growth delay and in the RIF-1 tumour by clonogenic cell survival 24 h after treatment and/or by growth delay. Toxicity to marrow stem cells was assayed 24 h after treatment, by the spleen colony technique. When drug was given at the start of heating, all drugs were potentiated both in tumour and marrow to varying degrees. However, there was no therapeutic gain for the combined treatment with DDP on RIF-1, with CCNU or BCNU on KHT, or with CHL on either RIF-1 or KHT. Therapeutic ratios for Mel of 1.9 to 2.0 for KHT and of 1.1 to 1.8 in RIF-1 were measured over the dose range 7.5 to 15.0 mg/kg in unheated animals, indicating net therapeutic gain under these conditions. An absolute therapeutic gain was found for Mel in KHT when Mel was given 30 min before the start of heat.

Animals↗
PubMed1990

Melphalan and prednisone (MP) versus vincristine, BCNU, adriamycin, melphalan and dexamethasone (VBAM Dex) induction chemotherapy and interferon maintenance treatment in multiple myeloma. Current results of a multicenter trial. The German Myeloma Treatment Group.

277 untreated multiple myeloma patients of stage 1 (n = 33), II (n = 106) and III (n = 138) entered the study. Patients of stage II presenting a progressive tumor (n = 64) initially or during observation (n = 14) were treated with MivP (remissions: 61%). 138 patients of stage III were randomized to receive MivP or VBAMDex treatment. 51% of MivP treated patients responded versus 70% of the VBAMDex group. 71 responders of stage II and III with stable disease were randomized on Ifn-alpha maintenance versus no maintenance treatment. The relapse rate in both groups was 50% after 7 months. 75% survival was greater than 36 months in stage II and 11 months in stage III patients.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1987

Approaches to defining the mechanism of enhancement by Fluosol-DA 20% with carbogen of melphalan antitumor activity.

Fluosol-DA with carbogen (95% oxygen and 5% carbon dioxide) breathing can increase the efficacy of melphalan. Addition of Fluosol-DA to treatment with melphalan leads to a greater increase in tumor growth delay under conditions of air breathing and carbogen breathing than does the fat emulsion Intralipid. The ability of melphalan to kill tumor cells increased with dose over the range of drug examined. At the lower doses of drug there is some increase in tumor cell killing seen with the addition of carbogen breathing or Fluosol-DA and air breathing; however, at the highest dose of the drug this difference disappeared. Throughout the melphalan dosage range examined there is approximately 1 log greater tumor cell kill observed with the addition of Fluosol-DA and carbogen breathing compared to the drug treatment alone. There was no significant difference in the survival of bone marrow cells under any of the treatment conditions. Fluosol-DA itself with air or carbogen breathing produced no detectable cross-links in DNA from tumors treated in vivo. The cross-linking factors for melphalan with air or carbogen breathing and for melphalan plus Fluosol-DA and air breathing were similar; when carbogen breathing was added to the treatment combination, the cross-linking factor increased almost 3-fold. When melphalan was dissolved in Fluosol-DA, the melphalan moved quickly into the lipophilic perfluorochemical particles so that after 1 h 60% of the drug was in the perfluorochemical layer. At 24 h, 85-90% of the melphalan was sequestered in the perfluorochemical particles. The pharmacokinetics of [14C]melphalan alone, [14C]melphalan plus Fluosol-DA, and [14C]melphalan prepared in Fluosol-DA were studied in several tissues of FSaIIC fibrosarcoma-bearing mice. In general, the tissue absorption and distribution t1/2s for melphalan were shortened in the presence of Fluosol-DA (except for kidneys). Shifting the t1/2s for absorption and distribution to shorter times produces a much sharper and earlier peak in the drug exposure of the tumor. Fluosol-DA provides a relatively nontoxic means of increasing oxygen delivery to tumors and a therapeutically meaningful way of improving melphalan antitumor activity.

Animals↗
PubMed1987

Facilitated transport of melphalan at the rat blood-brain barrier by the large neutral amino acid carrier system.

Melphalan has been reported to be actively transported into tumor cells by two amino acid carrier systems. As amino acids are transported across cerebral capillaries by a facilitated mechanism, studies were undertaken to assess whether or not melphalan was transported similarly, and additionally to determine melphalan's plasma and brain pharmacokinetics. The brain uptake of [14C]melphalan was measured by an in situ brain perfusion technique in the anesthetized rat utilizing [14C]-melphalan. The cerebrovascular permeability-surface area product of [14C]melphalan was calculated at cold melphalan concentrations from O to 16.3 mumol/ml. The permeability-surface area product was concentration dependent and decreased from 10.8 +/- 0.6 (+/- SE) X 10(-4)S-1 at 0.02 mumol/ml melphalan to 5.4 +/- 0.3 X 10(-4)S-1 at 16.3 mumol/ml. The system became saturated at a concentration in excess of 0.1 mumol/ml. The Michaelis-Menten parameters Vmax and Km, determined by nonlinear regression analysis of the permeability-surface area product data, equaled 0.9 +/- 0.3 X 10(-4) mumol/s/g and 0.15 +/- 0.06 mumol/ml, respectively, for the saturable component of melphalan's brain uptake. The Kd of the nonsaturable component was 5.3 +/- 0.03 X 10(-4)S-1. Addition of the amino acid 1-phenylalanine to the brain perfusate inhibited the saturable component of melphalan's brain uptake. The analysis of the plasma and brain concentrations of melphalan by high-performance liquid chromatography, following i.v. melphalan administration, demonstrated that approximately 15% of the drug that was present in plasma entered the brain. These data suggest that the brain uptake of melphalan is facilitated, demonstrating concentration-dependent uptake, saturation, and inhibition, and that melphalan shares the large neutral amino acid carrier system at the blood-brain barrier.

Amino Acids↗
PubMed1985

Verapamil potentiation of melphalan cytotoxicity and cellular uptake in murine fibrosarcoma and bone marrow.

Growth delay by melphalan of two fibrosarcomas in CBA mice was prolonged by intraperitoneal (i.p.) verapamil, 10 mg kg-1. Verapamil also increased the area under the blood concentration time curve and the gastrointestinal toxicity of melphalan. Verapamil promoted melphalan cytotoxicity to murine bone marrow both in vivo, by CFU-S assay, and in vitro, by CFU-GM assay. In 1 microgram ml-1 [14C]-melphalan, verapamil (10 micrograms ml-1) increased by 1.5 times the [14C]-melphalan accumulation by murine bone marrow, reversibly and independently of external calcium. Efflux of [14C]-melphalan from murine bone marrow was retarded by verapamil. Verapamil increased [14C]-melphalan uptake by disaggregated fibrosarcoma cells but had no effect on melphalan accumulation and cytotoxicity in human bone marrow. Although verapamil affected melphalan pharmacokinetics, enhancement of cellular melphalan uptake by verapamil in murine fibrosarcoma and bone marrow appeared to account for much of the increase in melphalan cytotoxicity. The lack of potentiation of melphalan by verapamil in human marrow suggests differences in melphalan transport or in verapamil membrane interactions in mouse and man.

Animals↗
PubMed1990

Pharmacokinetics of very high-dose oral melphalan in cancer patients.

The pharmacokinetics and systemic availability of melphalan after high-dose oral administration with and without 1,3-bis(2-Chloroethyl)-1-nitrosourea (BCNU) or etoposide were examined in three patients undergoing autologous bone marrow transplantation. Patient 1 (advanced melanoma) received melphalan at 80 mg/m2/day p.o. on days -6, -5, and -4, followed by BCNU at 300 mg/m2/day i.v. on days -3, -2, and -1 prior to bone marrow transplantation. Patient 2 (advanced colon carcinoma) received melphalan at 75 mg/m2/day p.o. on days -3, -2, and -1. Patient 3 (advanced refractory lymphoma) received etoposide at 800 mg/m2/day i.v. on days -7, -5, and -3, followed by melphalan at 157 mg/m2/day p.o. on days -2 and -1. Melphalan was administered as a bolus oral dose, using 2-mg tablets. Blood samples were collected at 0, 5, 10, 15, 30, and 45 min and 1, 2, 3, 4, 6, 8, 12, and 24 h after each dose of melphalan. Peak plasma melphalan concentrations in the three patients ranged from 0.354 (patient 2) to 1.768 micrograms/ml (patient 1). Plasma melphalan concentration X time products (C x Ts) showed extreme variability in one patient (patient 2), ranging from 0.76 to 4.48 micrograms.h/ml. To determine the relative systemic availability of orally administered melphalan, i.v. C X Ts proportional to the p.o. doses were extrapolated from previously reported i.v. bolus pharmacokinetic data. The p.o.:i.v. plasma C X T ratios for high-dose melphalan ranged between 0.09 (patient 3) and 0.58 (patient 2). Although these C X T data suggest a dose-response for orally administered melphalan, the systemic availability of these high p.o. melphalan doses was extremely variable, both within and between study patients. Thus, we cannot recommend the use of high-dose p.o. melphalan regimens in patients undergoing autologous bone marrow transplantation.

Adenocarcinoma↗
PubMed1985

Antagonism of the cytocidal activity and uptake of melphalan by tamoxifen in human breast cancer cells in vitro.

The effect of the antiestrogen tamoxifen on the cytocidal activity and uptake of melphalan in human breast cancer cells was investigated. A clonogenic assay was used to obtain dose-survival curves of estrogen receptor-positive MCF-7 cells and of estrogen receptor-negative Evsa T cells following treatment with melphalan and/or tamoxifen. Isobolograms derived from these dose-survival curves were concave downward, suggesting that the drug interaction was antagonistic. The effect of tamoxifen on melphalan uptake by breast cancer cells was evaluated at steady-state conditions. Thin-layer chromatography revealed that the intracellular level of free intact melphalan (mean +/- S.E.) in control cells was 6.47 +/- 1.21 fmoles/cell and that in cells treated with tamoxifen was 3.60 +/- 0.35 fmoles/cell; this 44% reduction in cellular melphalan was statistically significant (P = 0.006). Thus, the antagonistic cytocidal effect of melphalan and tamoxifen against breast cancer cells appeared to be due to inhibition of melphalan uptake at the steady state by the antiestrogen. Further investigation revealed that tamoxifen inhibited unidirectional melphalan influx in human breast cancer cells both by the sodium-independent system L and by the sodium-dependent system ASC. Tamoxifen also appeared to stimulate melphalan efflux from human breast cancer cells. The first-order rate constant K for melphalan efflux from control cells was 0.085 +/- 0.008 and that from cells treated with tamoxifen was 0.129 +/- 0.005; the difference was highly significant (P less than 0.001). Therefore, the antagonistic effect of tamoxifen on the uptake and cytocidal activity of melphalan in breast cancer cells appeared to be due to inhibition of melphalan influx and stimulation of drug efflux.

Breast Neoplasms↗
PubMed1986

Effects of verapamil and alcohol on blood flow, melphalan uptake and cytotoxicity, in murine fibrosarcomas and human melanoma xenografts.

Verapamil had previously been shown to increase cellular melphalan uptake and cytotoxicity in fibrosarcomas, and increased the area under the blood concentration versus time curve (AUC) for melphalan in CBA mice. Verapamil (10 mg kg-1 i.p.) had no effect on the fractional distribution of cardiac output (FDCO), measured with 86Rb-rubidium chloride, to subcutaneous fibrosarcomas. 14C-Melphalan uptake by FS13 fibrosarcomas was increased 60 min after verapamil (10 mg kg-1 i.p.), but not after lower doses which did not affect the AUC. Flunarizine (5 mg kg-1 i.p.) also had no effect on FDCO to FS13 fibrosarcomas, and tended to increase 14C-melphalan content of blood and the fibrosarcomas and to promote growth delay by melphalan. Alcohol increased FDCO to FS13 fibrosarcomas, maximally at a 1:20 dilution in saline, but had no effect on 14C-melphalan uptake or growth delay. Thus, melphalan cytotoxicity correlated with tumour melphalan uptake, and both followed changes in the AUC for melphalan but not changes in FDCO. In these murine fibrosarcomas melphalan uptake and cytotoxicity were not limited by blood flow. In subcutaneous human melanoma HX46 xenografts, verapamil had no effect on the FDCO, nor on 14C-melphalan uptake, and did not affect blood 14C-melphalan levels, suggesting absence of effects on the AUC and on cellular uptake. Alcohol did not increase the FDCO to HX46 xenografts, providing evidence for a different vascular supply.

Animals↗